Cyclosporine A, the active principal in NEORAL and SANDIMMUNE, is a cyclic polypeptide immunosuppressant agent. NEORAL and SANDIMMUNE are indicated for use in kidney, liver and heart transplantation, rheumatoid arthritis, and adult, non-immunocompromised patients with severe psoriasis. However, use of NEORAL and SANDIMMUNE has been linked to an increased susceptibility to infection and development of neoplasia, and more specifically with respect to SANDIMMUNE, development of lymphoma.
Cyclophilin proteins have been identified as the binding partners for the immunosuppressive agent cyclosporine. Cyclosporine A interacts with cyclophilins with high affinity, inhibiting their cis-trans peptidyl prolyl isomerase activity and the action of the phosphatase calcineurin, necessary for NF/AT-transactivated expression of IL-2 (Kronke et al. Proc. Natl Acad. Sci. USA 1984 81:5214; Liu et al. Cell 1991 55:807; Friedman, J. and Weissman, I. Cell 1991 66:799; McCaffrey et al. J. Biol. Chem. 1993 268:3747; Bram, R. J. and Crabtree, G. R. Nature 1994 371:355; Bram et al. Mol. Cell Biol. 1993 13:4760).
Cyclophilin B interacts specifically with somatolactogenic hormones, prolactin and growth hormone, as a chaperone mediating the transport, maturation and/or function of these proteins (Rycyzyn et al. Mol. End. 2000 14:1175-1186; Rycyzyn and Clevenger Proc. Natl Acad. Sci. USA 2002 99:6790-6795). These hormones are necessary for the full growth and maturation of vertebrate species.
Prolactin was originally identified as a neuroendocrine hormone of pituitary origin. Prolactin expression has also been detected in the decidua, breast and T-lymphocytes (Clevenger, C. V. and Plank, T. L. J. Mammary Gland Biol. Neoplasia 1997 2:59-68; Mershon et al. Endocrinology 1995 136:3619-3623; DiMattia et al. Endocrinology 1986 122:2508-2517; Ginsburg, E. and Vonderhaar, B. K. Cancer Res. 1995 55:2591-2595; Gellersen et al. Mol. Endocrinol. 1994 8:356-373; Clevenger et al. Proc. Natl Acad. Sci. USA 1990 87:6460-6464; Montogomery et al. Biochem. Biophys. Res. Commun. 1987 145:692-698). A primary function of this hormone lies within the breast. However, functional pleiotropism of this peptide with regard to reproduction, osmoregulation and behavior has also been recognized (Nicoll, C. S. Handbook of Physiology; Section 7: Endocrinology, pp. 253-292, Washington, D.C.: American Physiology Society. 1974). Several lines of evidence have also indicated an immunoregulatory role for this peptide (Clevenger et al. Journal of Endocrinology 1998 157:187-197; Weigent, D. A. Pharmacol. Ther. 1996 69:237-257). Structural analysis of prolactin has revealed it to be related to members of the cytokine/hematopoietin family which also includes growth hormone, erythropoietin, granulocyte-macrophage colony stimulating factor and interleukins 2-7 (Bazan, J. F. Immunol. Today 1990 11:350-354)
The pleiotropic actions of prolactin are mediated through its receptor (PRLr), a member of the superfamily of type I cytokine receptors. PRLr is present on numerous tissues including mammary epithelia, T and B lymphocytes and macrophages (Dardenne et al. Endocrinology 1994 134:2108-2114; Pellegrini et al. Mol, Endocrinol. 1992 6:1023-1031). Acting through its receptor, prolactin signaling stimulates cell proliferation, survival and cellular differentiation in a tissue- and microenvironment-dependent manner. In the mammary and immune systems, prolactin is believed to act at the endocrine, paracrine, and autocrine levels in regulating T-lymphocyte proliferation and survival (Gala, R. R. PSEBM 1991 198:513-527; Yu-Lee, L. Y. Proceedings of the Society for Experimental Biology and Medicine 1997 215:35-52; Kooijman et al. Adv. Immunol. 1996 63:377-454; Prystowski, M. B. and Clevenger, C. V. Immunomethods 1994 5:49-55) and the terminal maturation of mammary tissues (Kelly et al. Rec. Prog. Horm. Res. 1993 48:123-164; Shiu et al. Rec. Prog. Horm. res. 1987 43:277-289). Prolactin is also believed to act as both an endocrine and autocrine/paracrine progression factor for mammary carcinoma in both rodents and humans (Welsch, C. W. Cancer Res. 1985 45:3415-3443; Welsch, C. W. and Nagasawa, H. Cancer Res. 1977 37:951-963; Manni et al. Cancer Res. 1986 37:951-963; Malarkey et al. J. Clin. Endocrinol. Metab. 1983 56:673-677; Clevenger et al. Am. J. Pathol. 1995 146:1-11; Fields et al. Lab. Invest. 1993 68:354-360; Ormandy et al. J. Clin. Endocrinol. Metab. 1997 82:3692-3699; and Mertani et al. Int. J. Cancer 1998 79:202-22).
Cyclophilin A has also been demonstrated to interact directly with PRLr in in vitro binding assays and regulate prolactin signaling (Syed et al. Endocrine 2003 20(½): 83-89). This direct interaction occurred in the presence and absence of cyclosporine (Syed et al. Endocrine 2003 20(½): 83-89).